Journal
JOURNAL OF CELLULAR AND MOLECULAR MEDICINE
Volume 23, Issue 2, Pages 1152-1163Publisher
WILEY
DOI: 10.1111/jcmm.14015
Keywords
aminothiazoles; bone resorption; human PBMCs; lipopolysaccharide; microsomal prostaglandin E synthase-1; osteoclastogenesis; osteoclasts; periodontal ligament cells; prostaglandin E-2; RAW 264.7 cells
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Funding
- Swedish Research Council
- Swedish Patent Revenue Fund
- Swedish Dental Society
- Stockholm County Council
- Karolinska Institutet
- Loo and Hans Osterman foundation
- Maud Kuistila Memorial foundation
- Jane and Aatos Erkko foundation
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Inflammatory mediator prostaglandin E-2 (PGE(2)) contributes to bone resorption in several inflammatory conditions including periodontitis. The terminal enzyme, microsomal prostaglandin E synthase-1 (mPGES-1) regulating PGE(2) synthesis is a promising therapeutic target to reduce inflammatory bone loss. The aim of this study was to investigate effects of mPGES-1 inhibitors, aminothiazoles TH-848 and TH-644, on PGE(2) production and osteoclastogenesis in co-cultures of periodontal ligament (PDL) and osteoclast progenitor cells RAW 264.7, stimulated by lipopolysaccharide (LPS), and bone resorption in RANKL-mediated peripheral blood mononuclear cells (PBMCs). PDL and RAW 264.7 cells were cultured separately or co-cultured and treated with LPS alone or in combination with aminothiazoles. Multinucleated cells stained positively for tartrate-resistant acid phosphatase (TRAP) were scored as osteoclast-like cells. Levels of PGE(2), osteoprotegerin (OPG) and interleukin-6, as well as mRNA expression of mPGES-1, OPG and RANKL were analysed in PDL cells. PBMCs were treated with RANKL alone or in combination with aminothiazoles. TRAP-positive multinucleated cells were analysed and bone resorption was measured by the CTX-I assay. Aminothiazoles reduced LPS-stimulated osteoclast-like cell formation both in co-cultures and in RAW 264.7 cells. Additionally, aminothiazoles inhibited PGE(2) production in LPS-stimulated cultures, but did not affect LPS-induced mPGES-1, OPG or RANKL mRNA expression in PDL cells. In PBMCs, inhibitors decreased both osteoclast differentiation and bone resorption. In conclusion, aminothiazoles reduced the formation of osteoclast-like cells and decreased the production of PGE(2) in co-cultures as well as single-cell cultures. Furthermore, these compounds inhibited RANKL-induced bone resorption and differentiation of PBMCs, suggesting these inhibitors for future treatment of inflammatory bone loss such as periodontitis.
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